What’s going on? The Central Dogma sounds like the backbone of an entire discipline. If it’s really a “dogma” how come it gets refuted on a regular basis? If it’s really so “central” to the field of molecular biology then why hasn’t the field collapsed?
In order to answer these questions we need to understand what the Central Dogma actually means. It was first proposed by Francis Crick in a talk given in 1957 and published in1958 (Crick, 1958). In the original paper he described all possible directions of information flow between DNA, RNA, and protein. Crick concluded that once information was transferred from nucleic acid (DNA or RNA) to protein it could not flow back to nucleic acids. In other words, the final step in the flow of information from nucleic acids to proteins is irreversible.

Fig. 1. Information flow and the sequence hypothesis. These diagrams of potential information flow were used by Crick (1958) to illustrate all possible transfers of information (left) and those that are permitted (right). The sequence hypothesis refers to the idea that information encoded in the sequence of nucleotides specifies the sequence of amino acids in the protein.

Crick restated the Central Dogma of Molecular Biology in a famous paper published in 1970 at a time when the premature slaying of the Central Dogma by reverse transcriptase was being announced (Crick, 1970). According to Crick, the correct, concise version of the Central Dogma is ...

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. (F.H.C. Crick, 1970)

Announcing the (Premature) Death of the Central Dogma

The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein coding RNA (ncRNA) transcription in the higher eukaryotes and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of genetic regulatory systems in animals and plants may be incorrect.

Mattick, J.S. (2003) Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays 25:930-939.The central dogma, DNA makes RNA makes protein, has long been a staple of biology textbooks.... Technologies based on textbook biology will continue to generate opportunities in bioinformatics. However, more exciting prospects may come from new discoveries that extend or even violate the central dogma. Consider developmental biology. The central dogma says nothing about the differences between the cells in a human body, as each one has the same DNA. However, recent findings have begun to shed light on how these differences arise and are maintained, and the biochemical rules that govern these differences are only being worked out now. The emerging understanding of developmental inheritance follows a series of fundamental discoveries that have led to a realization that there is more to life than the central dogma.

Henikoff, S. (2002) Beyond the central dogma. Bioinformatics 18:223-225.It will take years, perhaps decades, to construct a detailed theory that explains how DNA, RNA and the epigenetic machinery all fit into an interlocking, self- regulating system. But there is no longer any doubt that a new theory is needed to replace the central dogma that has been the foundation of molecular genetics and biotechnology since the 1950s.

The central dogma, as usually stated, is quite simple: DNA makes RNA, RNA makes protein, and proteins do almost all of the work of biology.

Unfortunately, there’s second version of the Central Dogma that’s very popular even though it’s historically incorrect. This version is the simplistic DNA → RNA → protein pathway that was published by Jim Watson in the first edition of The Molecular Biology of the Gene (Watson, 1965). Watson’s version differs from Crick’s because Watson describes the two-step (DNA → RNA and RNA → protein) pathway as the Central Dogma. It has long been known that these conflicting versions have caused confusion among students and scientists (Darden and Tabery, 2005; Thieffry, 1998). I argue that as teachers we should teach the correct version, or, at the very least, acknowledge that there are conflicting versions of the Central Dogma of Molecular Biology.

The pathway version of the Central Dogma is the one that continues to get all the attention. It’s the version that is copied by almost all textbooks of biochemistry and molecular biology. For example, the 2004 edition of the Voet & Voet biochemistry textbook says,

In 1958, Crick neatly encapsulated the broad outlines of this process in a flow scheme he called the central dogma of molecular biology: DNA directs its own replication and its transcription to yield RNA, which, in turn, directs its translation to form proteins. (Voet and Voet, 2004)

If the Watson pathway version of the Central Dogma really was the one true version then it would have been discarded or modified long ago. In his original description, Watson drew single arrows from DNA to RNA and from RNA to protein and stated ....

The arrow encircling DNA signifies that it is the template for its self-replication; the arrow between DNA and RNA indicates that all cellular RNA molecules are made on DNA templates. Most importantly, both these latter arrows are unidirectional, that is, RNA sequences are never copied on protein templates; likewise, RNA never acts as a template for DNA.

Fig. 2. Watson’s version of the Central Dogma. This figure is taken from the first edition of The Molecular Biology of the Gene (p. 298).

Watson's statement is clearly untrue, as the discovery of reverse transcriptase demonstrated only a few years after his book was published. Furthermore, there are now dozens of examples of information flow pathways that are more complex than the simple scheme shown in Watson’s 1965 book. (Not to mention the fact that many information flow pathways terminate with functional RNA’s and never produce protein.)

Watson’s version of the Central Dogma is the one scientists most often refer to when they claim that the Central Dogma is dead. The reason it refuses to die is because it is not the correct Central Dogma. The correct version has not been refuted.

Crick was well aware of the difference between his (correct) version and the Watson version. In his original 1958 paper, Crick referred to the standard information flow pathway as the sequence hypothesis. In his 1970 paper he listed several common misunderstandings of the Central Dogma including ....

It is not the same, as is commonly assumed, as the sequence hypothesis, which was clearly distinguished from it in the same article (Crick, 1958). In particular, the sequence hypothesis was a positive statement, saying that the (overall) transfer nucleic acid → protein did exist, whereas the central dogma was a negative statement saying that transfers from protein did not exist.

The Sequence Hypothesis and the Central Dogma in 1957

My own thinking (and that of many of my colleagues) is based on two general principles, which I shall call the Sequence Hypothesis and the Central Dogma. The direct evidence for both of them is negligible, but I have found them to be of great help in getting to grips with these very complex problems. I present them here in the hope that others can make similar use of them. Their speculative nature is emphasized by their names. It is an instructive exercise to attempt to build a useful theory without using them. One generally ends in the wilderness.

The Sequence Hypothesis. This has already been referred to a number of times. In its simplest form it assumes that the specificity of a piece of nucleic acid is expressed solely by the sequence of its bases, and that this sequence is a (simple) code for the amino acid sequence of a particular protein.

This hypothesis appears to be rather widely held. Its virtue is that it unites several remarkable pairs of generalizations: the central biochemical importance of proteins and the dominating role of genes, and in particular of their nucleic acid; the linearity of protein molecules (considered covalently) and the genetic linearity within the functional gene, as shown by the work of Benzer and Pontecorvo; the simplicity of the composition of protein molecules and the simplicity of nucleic acids. Work is actively proceeding in several laboratories, including our own, in an attempt to provide more direct evidence for this hypothesis.

The Central Dogma. This states that once “information” has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.

So, how do we explain the current state of the Central Dogma? The Watson version is the one presented in almost every textbook, even though it is not the correct version according to Francis Crick. The Watson version has become the favorite whipping boy of any scientist who lays claim to a revolutionary discovery, even though a tiny bit of research would uncover the real meaning of the Central Dogma of Molecular Biology. The Watson version has been repeatedly refuted or shown to be incomplete, and yet it continues to be promoted as the true Central Dogma. This is very strange.

The Crick version is correct—it has never been seriously challenged—but few textbooks refer to it. One exception is Lewin’s GENES VIII (Lewin, 2004) (and earlier editions). Lewin defines the Central Dogma of Molecular Biology as,

The central dogma states that information in nucleic acid can be perpetuated or transferred but the transfer of information into protein is irreversible. (B. Lewin, 2004)

I recommend that all biochemistry and molecular biology teachers adopt this definition—or something very similar—and teach it in their classrooms.

36 comments
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In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.

The qualifier that information refers to sequence (rather than structure) protects against this, but prions appear to be nearly violate the central dogma as they transfer information between proteins.

And what about post-transcriptional modification of RNAs by proteins? Or post-translational modifications of protein sequences?

I was (again) very confused about the background to the presented basic information. This confusion centered around, of course, the two versions of the dogma, but also why some information transfers must be "permitted" instead of merely observed.

Is this about explicitly excluding the possibilities of non-observed Lamarckism one wonders? But the mystery is revealed much further down when Crick makes the statement RPM refers to, and makes "information" precise, and the meaning of his formulation clear.

Btw, the two versions bugs me too. I took a course in molecular biology way back. (For fun, being one of several alternative courses meant to build perspective on the basic engineering/physics curricula.)

The memory is by now weak indeed, but I can't remember that Crick's version was even mentioned...

Sorry, I was a little trigger happy there. The article I'm trying to link to is called "Chemical Crosshairs on the Central Dogma", published in this months Nature Chemical Biology. It can be freely read at this site:

Thanks Larry. This ambiguity causes no end of problems for students, some scientists who should know better and of course creationists who just love to muddy the waters. Some of the confusion also arises from a failure for us looking back now, to fully appreciate the historical context in which the central dogma was first presented. At the time, Crick was painfully aware that the direct evidence for his proposal was very low and he wanted to emphasise this point.

“My own thinking (and that of many of my colleagues) is based on two general principles, which I shall call the Sequence Hypothesis and the Central Dogma. The direct evidence for which is negligible, but I have found them to be of great help in getting to grips with these very complex problems.”

Crick’s caution also sheds light on why he used the word ‘dogma’ – a strange word to use in a scientific context. Horace Freeland asked Crick about this in ‘The Eighth Day of Creation’:

“Why had he called it the central dogma? “Ah! That’s a very, very interesting thing! It was because, I think, of my curious religious upbringing.” He moved in his chair. “Because Jacques (Monod) has since told me that a dogma is something which a true believer cannot doubt!” Crick laughed. “And indeed, a friend said to me the same thing at dinner last night…. But that wasn’t what was in my mind. My mind was, that a dogma was an idea for which there was no reasonable evidence. You see?! And Crick gave a roar of delight. “I just didn’t know what dogma meant. And I could just as well have called it the ‘Central Hypothesis’, or – you know. Which is what I meant to say. Dogma was just a catch phrase”.

Re Crick's definition of "information" - What is the reason for (usefulness of) restricting the definition to the determination of sequence? Proteins can promote or inhibit the production of other proteins; is there any evidence at all that proteins can cause a particular coding sequence to produce more than one protein (i.e., different amino acid sequences), e.g., by affecting which parts of the coding sequence act as introns vs. exons?

This was a very informative article, as a student myself I have found the central dogma to be rather confusing. Its importance, to me, seemed to be its refutation of Lamarckian principles (e.g. rabbits cannot pass their aquired immunities on to their children via the genetic code) for which Crick's definition works well. This, however, does not sit as well with Watson's definition, and I don't think the distinction between the two is widely known (or at least, not as well known as it should be...)

jud: "is there any evidence at all that proteins can cause a particular coding sequence to produce more than one protein (i.e., different amino acid sequences), e.g., by affecting which parts of the coding sequence act as introns vs. exons?"

This is alternative splicing, and it happens all the time. Spliceosomes do the splicing, but they are complexes of proteins and RNA. I know nothing about how alternative splicing is regulated.

p.s. Forgot to mention that the discovery of alternative splicing prompted Barry Commoner to declare the Death of the Central Dogma in an article in Harper's about 5 years ago...he also opined (as I recall) that genetic engineering was a waste of time, in part because we could never understand the complexity of expression-regulatory networks.

I've been pestering molecular biologists for years about this very point, and arguing that scientists who aren't taught the history of their discipline are only half educated.

And, to the extent that intellectual role models are important, scientists couldn't do better than to emulate Crick. For example, he was very clear about how he was using the term 'information,' and tying it to a particular problematic -- what he called the problem of 'sequentialization.' This is a far cry from the vague appeals to 'biological information' one encounters at every turn today.

It is precisely because of ambiguities in Biologists' use of the word "information" that I have done and published considerable research. My Doctoral research 1973-1977 at U.Mass./Amherst spun off several refereed Mathematical Biology papers on equations governing information flow in metabolic systems. A current draft paper is on a model of the Shannon channel capacity of evolution by natural selection.

See this in wiki at:http://necsi.org/community/wiki/index.php?title=Evolutionary_channel_capacity&redirect=no

Traditionally, the problem was that Biologists didn't know Information Theory, and vice versa. But that was decades ago. The problem now is in fitting the explosion of genomic, proteomic, transcriptomic, metabolomic, lipidomic, and chronomic data to mathematical models, and trying to explain it all to students, colleagues, granting agencies, and the press.

"This states that once ‘information’ has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein. (Crick 1958, 152-153, emphasis in original)"

Doesn't alternative splicing contradicts this? (as it was suggested in a previous post?)

Regarding the definition used for "information" .....

Proteins can indeed modulate the "precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein. ", by altering the final sequence in an mature mRNA molecule derived from a specific locus and the specific amino acids that will then be incorporated in the protein, when compared to the other alternatively spliced form (in the specific cases where this happens).

They can even (in some cases) regulate their own splicing (and mature mRNA sequence).

I believe that what Anonymous wanted to say is that a protein can regulate the final outcome of an mRNA.So what I guess he thought is that a protein could indeed modulate the "precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein. " as stated in the dogma. So, the info could indeed come from a protein, regulating another mRNA.

They do occur before a protein is generated, but once it is generated, those proteins could determine information, by altering the final outcome of another mRNA molecule by regulating its splicing or editing.

"1000 Genomes pilot a hit with geneticists"The first stage of a project to probe human genetic diversity has found millions of new variations.http://www.sciencenews.org/view/generic/id/64761/title/1000_Genomes_pilot_a_hit_with_geneticists

For probing human DNA genetic diversity bear in mind that:

"PERO SE MOVERA EARTH LIFE HAS ALWAYS BEEN AND STILL IS AN RNA WORLD"http://www.the-scientist.com/community/posts/list/320/122.page#6472

C. It's not the protein that makes the enzyme. It's the RNA that has evolved the protein. AND IT'S THE RNAs THAT HAVE EVOLVED AND PRODUCE AND EMPLOY THE DNA templates to carry out life processes, for enhancing Earth's biosphere, for enhancing and constraining as long as possible some energy, some of the total energy of the universe, all of which destined to fuel the ongoing cosmic expansion.

- Dark energy and matter YOK. Per E=Total[m(1 + D)] all the energy and matter of the universe are accounted for.

- Higgs Particle YOK. Mass begins to form at some value of the above D.

- Sleep is inherent for life via the RNAs, the primal Earth ORGANISMS formed and active only under direct sunlight in pre-metabolism genesis era.

- Natural selection is ubiquitous for ALL Mass Formats. It derives from the expansion of the universe.

- Epigenetics: Where Life Meets the Genomehttp://www.bionews.org.uk/page_66997.asp?dinfo=rWfnKzZO4tkhJf38jsJ5EeJo

Epigenetics = a) the study of heritable changes in gene function that do not involve changes in DNA sequenceb) the science of enduring changes in the pattern of gene activity, during embryo development and beyond, that do not involve alteration of the DNA sequence.

The "heritable or enduring changes" are epiDNAtics, not epigenetics. Alternative splicing is not epigenetics, even if/when not involving alteration of the DNA sequence. Earth life is an RNA world.

It's the RNAs that evolve proteins. AND IT'S THE RNAs THAT HAVE EVOLVED AND PRODUCE AND EMPLOY THE DNA templates to carry out life processes, for enhancing Earth's biosphere, for enhancing and constraining as long as possible some energy, some of the total energy of the universe, all of which is destined to fuel the ongoing cosmic expansion.

Dr. Moran said:"Alternative splicing and RNA editing are processes that occur before information passes from nucleic acid to protein. "

I keep hearing about splicing regulatory networks from grad student friends studying splicing, and I believe that the existence of specific splicing factor isoforms regulating specific splicing/editing events has been found. This demonstrates the flow of information from nucleic acid to protein, and back to nucleic acid. Thus I think this would contradict the "correct" statement of the central dogma. Just my two cents.

Thank you very much for elucidating the defination of Central Dogma because it was indeed confusing because different literature comes with their own defination.The reason protein cannot be converted back to RNA is because of rendundacy since one codon can code for two to three different amono acids.This makes it impossible for protein to be converted to RNA

Great post, thank you. I'd never even heard of Crick's version before - every source I'd encountered simply gave the DNA->RNA->Protein version as the "Central Dogma", usually accrediting it to Crick along the way. I thought it continued to be used as it is still broadly correct - yes there is RNA->DNA flow but it's a smaller part of the picture.

Er, the central dogma is toast. Sequence information can and does go back into the genome - in genetic engineering. You can reverse engineer protein residues (e.g. from Dinosaurs) and synthesize them - to see if they really do taste like chicken. Here is James Gardner (1999) on the topic:

"to a degree that is largely unappreciated by orthodox theoretical biologists, the ongoing revolution in biotechnology renders the central dogma obsolete. The fact is that information can and does flow upstream into the genome"

That's a bit different from it happening in nature. Also, how could the original nucleotide sequence possibly be recovered, given the redundancy in coding for amino acids? There would necessarily have to be a loss of information.

I'm sorry that you didn't understand some basic concepts in the field even after working on them for twenty years. You are not alone, there are many other people like you who are confused about noncoding DNA, evolution, and the fact that most of our genome is junk.

The good news is that it's not too late to learn! In order to prevent this sort of thing from happening again, we need to make sure that the current crop of students is taught correctly.

Laurence A. Moran

Larry Moran is a Professor in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

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Quotations

The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Quotations

The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

Quotations

My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick
There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.